Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| FD-R-0005380 | Other Grant/Funding Number | FDA Office of Orphan Products Development |
Not provided
Not provided
funding ended
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| University of Alabama at Birmingham | OTHER |
| Children's Hospital of Philadelphia | OTHER |
| Johns Hopkins University | OTHER |
| Horizon Pharma Ireland, Ltd., Dublin Ireland |
Not provided
Not provided
Not provided
Not provided
We propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy (PERT) on absorption of Ravicti® and subsequent restoration of nasal epithelial cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride transport during the nasal potential difference (NPD) test. Funding source FDA Office of Orphan Products Development.
We were the first to test 4-phenylbutyrate (Buphenyl) as a systemic corrector of these defects in F508del under an investigator-initiated Investigational New Drug (IND)application held by P. Zeitlin. In a series of Phase 1 and 2 trials we established the maximum tolerated dose as 20 gm daily divided t.i.d. and the maximum induction of cyclic AMP (cAMP)-mediated nasal epithelial chloride transport with 30 gm daily as a median of -10 millivolt (mV) on days 4 and 7 of treatment.1;2 Under those conditions there was no significant decrease in sweat chloride values or in amiloride-inhibited nasal potential difference (NPD). We interpreted these results as a proof of concept of corrector therapy, but corrector therapy alone was likely an insufficient therapy for this mutation in CF, and therefore closed the IND for 4-phenylbutyrate.
In the ensuing years, Vertex Pharmaceuticals, Inc. has had success with the development of ivacaftor3;3;4 (VX-770) as a potentiator of G551D CFTR and has studied the drug alone and in combination with their corrector lumacaftor5 (VX-809) and VX-661. We at Johns Hopkins University (JHU), University of Alabama at Birmingham (UAB) and Childrens' Hospital of Philadelphia/University of Pennsylvania (CHOP/Penn) have participated in many of the clinical trials and are pleased and encouraged by the success of VX-770. It is not yet certain that future combinations of corrector(s) and potentiator(s) will be safe and effective, and it is prudent to explore alternative correctors and potentiators. Furthermore, recent structural investigations in a number of laboratories support the idea that more than one corrector may be necessary to fully restore F508del to the trafficking pathway 6. Precedent for combination of 4PBA with other CFTR modulators has been established in vitro 7;8 4-Phenylbutyrate tablets are formulated for oral delivery, and we showed that the pharmacokinetics were similar in CF to that in patients with urea cycle disorders. However the large number of tablets that had to be ingested at each meal were somewhat daunting at the 30 gm daily dose. A new pro-drug of 4-phenylbutyrate, glycerol phenylbutyrate or Ravicti®(owned by Hyperion Pharmaceuticals, Inc.) was approved in February 2013 by the US FDA. This new formulation is a significant advance for patients with urea cycle disorders because it is an oral, odorless, tasteless liquid, that contains 3 molecules of 4-phenylbutyrate for every molecule of the triglyceride. Simple arithmetic would suggest that one mole equivalent of the pro-drug provides three moles of active drug. However, pancreatic lipase enzymes are required to break the covalent bonds and release the active drug in the intestines. Because most CF patients homozygous for F508del are pancreatic-insufficient and already on enzyme therapy, we propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy (PERT) on absorption of Ravicti® and subsequent restoration of nasal epithelial CFTR-mediated chloride transport during the nasal potential difference (NPD) test.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ravicti low dose | Active Comparator | Low dose Ravicti® oral liquid at 6ml (6.6 gm) by mouth or gastrostomy tube at 8 am, 5.5 ml (6.05gm) at 4pm and midnight for 7 days. |
|
| Placebo | Placebo Comparator | Matching placebo taken at 8am, 4pm and midnight for 7 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ravicti low dose | Drug | 8 am, 4pm and midnight |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Chloride and Sodium Transport in Nasal Epithelium | Change in average measurement of nasal potential difference in millivolts (mV) between baseline (Visit 0) and Day 4 (Visit 2) or Day 7 (Visit 3). Note: the outcome is assessed as change in mV at each visit, and then comparisons between visits are made. | 7 days |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Average Sweat Chloride | Change in average sweat chloride measurement between baseline Day 1 (Visit 1) and Day 7 (Visit 3). | 7 days of treatment as measured on Day 1 (Visit 1) and Day 7 (Visit 3) |
| Change in Baseline Nasal Potential Difference (NPD) |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics (PK) Studies | Concentration of PBA and PAA in blood over time | 4 days |
Inclusion Criteria:
Male or female ≥ 18 years of age.
Confirmed diagnosis of CF based on the following criteria:
any CFTR genotype combination EXCEPT two stop codons, and one or more clinical features consistent with the CF phenotype.
Taking pancreatic enzyme replacement therapy (PERT), or have documented pancreatic sufficiency.
Ability to perform acceptable spirometry.
Ability to understand and sign a written informed consent and comply with the requirements of the study.
FEV1 ≥30% of predicted normal for age, gender, and height (Hankinson standards): pre or post-bronchodilator at Screening.
Oxygen saturation by pulse oximetry ≥90% breathing either ambient air or regular oxygen regimen at screening and Day 1.
Hematology and clinical chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments (as judged by the principal investigator) at screening. If electrolyte abnormality at screening, values must be corrected prior to dosing.
Subjects on chronic inhaled antibiotic therapy are eligible if they can continue their usual antibiotic regimen, or remain on their off-cycle period, for the duration of study drug exposure
Negative pregnancy test for women of child-bearing potential.
If of childbearing potential, agree to use one highly effective method of contraception from the time of consent through the Visit 4 study visit, per section 9.1.13 of the protocol.
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Pamela L Zeitlin, MD, PhD | National Jewish Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Jewish Health | Denver | Colorado | 80206 | United States | ||
| Johns Hopkins University School of Medicine |
Not provided
| Label | URL |
|---|---|
| Johns Hopkins CF research office | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Ravicti Low Dose | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 1.1 gm/ml 11 subjects started 9 subjects completed 2 subjects had a serious adverse event 0 subject deaths |
| FG001 | Placebo | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 5 subjects started 5 subjects completed 0 subjects had a serious adverse event 0 subject deaths |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Ravicti Low Dose | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 1.1 gm/ml 9 subjects between 18-65 |
| BG001 | Placebo | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 5 subjects between 18-65 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Chloride and Sodium Transport in Nasal Epithelium | Change in average measurement of nasal potential difference in millivolts (mV) between baseline (Visit 0) and Day 4 (Visit 2) or Day 7 (Visit 3). Note: the outcome is assessed as change in mV at each visit, and then comparisons between visits are made. | Posted | Least Squares Mean | Standard Error | mV | 7 days |
|
14 days
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ravicti Low Dose | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 1.1 gm/ml 9 subject were at risk and 3 subjects had an adverse event. Adverse events were headache, brain fog, nausea/vomiting/flatulence, and new sputum bacteria. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cystic Fibrosis Pulmonary Exacerbation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headache | Nervous system disorders | Systematic Assessment |
Early termination leading to small numbers of subjects analyzed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pamela L. Zeitlin, Chair, Department of Pediatrics | National Jewish Health | 303-398-1196 | zeitlinp@njhealth.org |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 18, 2021 | Oct 25, 2024 | Prot_SAP_000.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D003550 | Cystic Fibrosis |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C570223 | glycerol phenylbutyrate |
Not provided
Not provided
Not provided
| INDUSTRY |
Not provided
Not provided
Not provided
Not provided
| Placebo | Drug | 8 am, 4pm and midnight |
|
Change in baseline nasal potential difference (NPD) measured before initiation of study drug between Day 1 (Visit 1) and Day 4 (Visit 2) and between Day 1 (Visit 1) and Day 7 (Visit 3). |
| 4 days and 7 days of study drug treatment |
| Change in Nasal Potential Difference With Perfusion of a Solution Containing Amiloride | Change in the nasal potential difference response (in mV) with perfusion of a solution containing amiloride from baseline to Days 4 and 7. | 4 and 7 days |
| Change in Nasal Potential Difference During Perfusion With a Low Chloride Solution Containing Amiloride | Change in nasal potential difference (in mV) with perfusion of a low chloride solution containing amiloride from baseline to Days 4 and 7. | 4 and 7 days |
| Change in Nasal Potential Difference With a Low Chloride Solution Containing Amiloride Plus the Change With a Low Chloride Solution Containing Amiloride and Isoproterenol | Change in Nasal Potential Difference (in mV} with perfusion of a low chloride solution (containing amiloride) followed by the low chloride solution containing amiloride and Isoproterenol from baseline to Days 4 and 7. | 4 and 7 days |
| Change in FEV1 | Change in FEV1 from baseline to Days 4 and 7. | 7 days |
| Safety and Tolerability - Electrolytes (Meq/L) | Electrolytes are presented in meq/L. Mean and SD reported at Screening and V4. | 14 days |
| Safety and Tolerability-Liver Function-Total Bilirubin | Total Bilirubin on a comprehensive metabolic panel obtained from a serum sample and reported in mg/dl. | 14 days |
| Safety and Tolerability - Liver Function-Liver Enzymes | Hepatic enzymes obtained from a serum sample -AST and ALT in units/L. | 14 days |
| Safety and Tolerability - Liver Function-Alkaline Phosphatase (IU/L) | Alkaline Phosphatase obtained on a Comprehensive Metabolic Panel (IU/L). | 14 days |
| Safety and Tolerability - Blood Protein Biomarkers (g/dl) | Safety and Tolerability - serum protein biomarkers in g/dl. | 14 days |
| Safety and Tolerability - Blood Cell Counts (K/ul) | White blood cells, red blood cells, and platelet cell counts from a complete blood cell count panel (K/ul). | 14 days |
| Safety and Tolerability - Blood Cell Counts (%) | White blood cells are fractionated into different types of white blood cells and presented as the fraction of total white blood cells counted. | 14 days |
| Safety and Tolerability - Erythrocyte Sedimentation Rate (mm/hr) | Erythrocyte sedimentation rate is an indicator of inflammation that measures the rate at which red blood cells settle to the bottom of a test tube in mm/hr. | 14 days |
| Safety and Tolerability - Serum Glucose (mg/dl) | Serum glucose was obtained in a comprehensive metabolic panel in mg/dl. | 14 days |
| Safety and Tolerability - Blood Waste Metabolites (mg/dl) | Blood urea nitrogen (BUN), serum creatinine, and serum uric acid were obtained in a comprehensive metabolic panel in mg/dl. | 14 days |
| Safety and Tolerability - Blood Biomarker of Inflammation (mg/dl) | C reactive protein (cRP) is a systemic marker of inflammation and was measured in mg/dl. | 14 days |
| Safety and Tolerability - Hematocrit (%) | Hematocrit is resulted as the fraction of red blood cells in total volume of blood from which they are measured. | 14 days |
| Baltimore |
| Maryland |
| 21205 |
| United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
|
|
| Secondary | Change in Average Sweat Chloride | Change in average sweat chloride measurement between baseline Day 1 (Visit 1) and Day 7 (Visit 3). | Posted | Least Squares Mean | Standard Error | mmol/L | 7 days of treatment as measured on Day 1 (Visit 1) and Day 7 (Visit 3) |
|
|
|
|
| Secondary | Change in Baseline Nasal Potential Difference (NPD) | Change in baseline nasal potential difference (NPD) measured before initiation of study drug between Day 1 (Visit 1) and Day 4 (Visit 2) and between Day 1 (Visit 1) and Day 7 (Visit 3). | Posted | Least Squares Mean | Standard Error | mV | 4 days and 7 days of study drug treatment |
|
|
|
|
| Secondary | Change in Nasal Potential Difference With Perfusion of a Solution Containing Amiloride | Change in the nasal potential difference response (in mV) with perfusion of a solution containing amiloride from baseline to Days 4 and 7. | Ravicti high dose was ultimately not tested in the clinical trial. | Posted | Least Squares Mean | Standard Error | mV | 4 and 7 days |
|
|
|
|
| Secondary | Change in Nasal Potential Difference During Perfusion With a Low Chloride Solution Containing Amiloride | Change in nasal potential difference (in mV) with perfusion of a low chloride solution containing amiloride from baseline to Days 4 and 7. | Posted | Least Squares Mean | Standard Error | mV | 4 and 7 days |
|
|
|
|
| Secondary | Change in Nasal Potential Difference With a Low Chloride Solution Containing Amiloride Plus the Change With a Low Chloride Solution Containing Amiloride and Isoproterenol | Change in Nasal Potential Difference (in mV} with perfusion of a low chloride solution (containing amiloride) followed by the low chloride solution containing amiloride and Isoproterenol from baseline to Days 4 and 7. | Posted | Least Squares Mean | Standard Error | mV | 4 and 7 days |
|
|
|
|
| Secondary | Change in FEV1 | Change in FEV1 from baseline to Days 4 and 7. | Posted | Least Squares Mean | Standard Error | Liters | 7 days |
|
|
|
|
| Secondary | Safety and Tolerability - Electrolytes (Meq/L) | Electrolytes are presented in meq/L. Mean and SD reported at Screening and V4. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | meq/L | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability-Liver Function-Total Bilirubin | Total Bilirubin on a comprehensive metabolic panel obtained from a serum sample and reported in mg/dl. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | mg/dl | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Liver Function-Liver Enzymes | Hepatic enzymes obtained from a serum sample -AST and ALT in units/L. | Two participants, one from Drug and one from Placebo groups failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | units/L | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Liver Function-Alkaline Phosphatase (IU/L) | Alkaline Phosphatase obtained on a Comprehensive Metabolic Panel (IU/L). | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | IU/L | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Blood Protein Biomarkers (g/dl) | Safety and Tolerability - serum protein biomarkers in g/dl. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | g/dl | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Blood Cell Counts (K/ul) | White blood cells, red blood cells, and platelet cell counts from a complete blood cell count panel (K/ul). | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | K/uL | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Blood Cell Counts (%) | White blood cells are fractionated into different types of white blood cells and presented as the fraction of total white blood cells counted. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | % of blood cells counted | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Erythrocyte Sedimentation Rate (mm/hr) | Erythrocyte sedimentation rate is an indicator of inflammation that measures the rate at which red blood cells settle to the bottom of a test tube in mm/hr. | One participant in the Drug group failed to have an ESR on screening, and one participant Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | mm/hr | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Serum Glucose (mg/dl) | Serum glucose was obtained in a comprehensive metabolic panel in mg/dl. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | mg/dl | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Blood Waste Metabolites (mg/dl) | Blood urea nitrogen (BUN), serum creatinine, and serum uric acid were obtained in a comprehensive metabolic panel in mg/dl. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | mg/dl | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Blood Biomarker of Inflammation (mg/dl) | C reactive protein (cRP) is a systemic marker of inflammation and was measured in mg/dl. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | mg/dl | 14 days |
|
|
|
|
| Secondary | Safety and Tolerability - Hematocrit (%) | Hematocrit is resulted as the fraction of red blood cells in total volume of blood from which they are measured. | One participant from Drug failed to return on day 14 and those data are missing. | Posted | Mean | Standard Deviation | % of packed red blood cell volume | 14 days |
|
|
|
|
| Other Pre-specified | Pharmacokinetics (PK) Studies | Concentration of PBA and PAA in blood over time | Posted | Least Squares Mean | Standard Error | micrograms/ml | 4 days |
|
|
|
|
| 0 |
| 9 |
| 2 |
| 9 |
| 2 |
| 9 |
| EG001 | Placebo | 6.0 ml po 8 AM, 6.05 ml 4 PM, 6.05 ml 12 AM 5 subject were at risk and 4 subjects had an adverse event. Adverse events were headache, brain fog, nausea/vomiting/flatulence, and new sputum bacteria. | 0 | 5 | 0 | 5 | 4 | 5 |
| Covid-19 | Infections and infestations | Systematic Assessment |
|
| brain fog | Nervous system disorders | Systematic Assessment |
|
| nausea, vomiting, flatulence | Gastrointestinal disorders | Systematic Assessment |
|
| new sputum bacteria | Infections and infestations | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007232 | Infant, Newborn, Diseases |
Standard hypothesis test. Null hypothesis: Mean change from Visit 1 to Visit 3 for drug group (LD) is equivalent to mean change from Visit 1 to Visit 3 for placebo (P) group; Alternative hypothesis: two-sided difference. |
Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 2 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Change in baseilne NPD, baseline (Visit 0) to Day 7 (Visit 3) | Mixed Models Analysis | The specific test is a t-test derived from the linear mixed model fit. | 0.065 | Interaction | -12.3 | Standard Error of the Mean | 6.4 | 2-Sided | 95 | -25.4 | 0.8 | The interaction estimate is the mean change for the drug group (LD) versus Placebo (P) from V0 to V3. Specifically, it is [Mean bl NPD, V3 for LD - Mean bl NPD, V0 for LD] - [Mean bl NPD, V3 for P - Mean bl NPD, V0 for P]. | Other | Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 3 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 3 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Other |
Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 2 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Change in nasal potential difference in mV with perfusion with amilioride, baseline (Visit 0) to Day 7 (Visit 3); all changes over time are taken as post minus pre, as noted below. | Mixed Models Analysis | Comments The specific test is a t-test derived from the linear mixed model fit. | 0.39 | Interaction | 5.3 | Standard Error of the Mean | 6.1 | 2-Sided | 95 | -7.1 | 17.8 | The interaction estimate is the mean change for the drug group (LD) versus Placebo (P) from V0 to V3: [Mean amilioride NPD, V3 for LD - Mean amilioride NPD, V0 for LD] - [Mean amilioride NPD, V3 for P - Mean amilioride NPD, V0 for P] | Other | Mean change from Visit 0 to Visit 2 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference. |
Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 2for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Change in Low Chloride, V0 to V3; all changes over time are taken as post minus pre, as noted below. | Mixed Models Analysis | The specific test is a t-test derived from the linear mixed model fit. | 0.91 | Interaction | -0.5 | Standard Error of the Mean | 4.4 | 2-Sided | 95 | -9.6 | 8.6 | The interaction estimate is the mean change for the drug group (LD) versus Placebo (P) from V0 to V3. Specifically, it is [Mean low chloride, V3 for LD - Mean low chloride, V0 for LD] - [Mean low chloride, V3 for P - Mean low chloride, V0 for P] | Other | Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 3 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 3 for placebo (P) group; Alternative hypothesis: two-sided difference. |
Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 2 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Change in Low Chloride plus Isoproterenol, V0 to V3; all changes over time are taken as post minus pre, as noted below. | Mixed Models Analysis | The specific test is a t-test derived from the linear mixed model fit. | 0.10 | Interaction | 4.3 | Standard Error of the Mean | 2.5 | 2-Sided | 95 | -0.9 | 9.4 | The interaction estimate is the mean change for the drug group (LD) versus Placebo (P) from V0 to V3: [Mean low chl + isop, V3 for LD - Mean low chl + isop, V0 for LD] - [Mean low chl + isop, V3 for P - Mean low chl + isop, V0 for P] | Other | Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 3 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 3 for placebo (P) group; Alternative hypothesis: two-sided difference. |
Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 2 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 2 for placebo (P) group; Alternative hypothesis: two-sided difference.
| FEV1, V0 to V3; all changes over time are taken as post minus pre, as noted below. | Mixed Models Analysis | The specific test is a t-test derived from the linear mixed model fit. | 0.36 | Interaction | 2.1 | Standard Error of the Mean | 2.3 | 2-Sided | 95 | -2.6 | 6.9 | The interaction estimate is the mean change for the drug group (LD) versus Placebo (P) from V0 to V3. Specifically, it is [Mean FEV1, V3 for LD - Mean FEV1, V0 for LD] - [Mean FEV1, V3 for P - Mean FEV1, V0 for P] | Other | Standard hypothesis test. Null hypothesis: Mean change from Visit 0 to Visit 3 for drug group (LD) is equivalent to mean change from Visit 0 to Visit 3 for placebo (P) group; Alternative hypothesis: two-sided difference. |
| Sodium (meq/l), 14 days |
|
|
| Potassium (meq/l), Screening |
|
|
| Potassium (meq/l), 14 days |
|
|
| Chloride (meq/l), Screening |
|
|
| Chloride (meq/l), 14 days |
|
|
| Bicarbonate/CO2 (meq/l), Screening |
|
|
| Bicarbonate/CO2 (meq/l), 14 days |
|
|
| 0.5351 |
| Other |
t-test for mean difference between groups |
| Potassium, Screening time point | t-test, 2 sided | 0.9251 | Other | t-test for mean difference between groups |
| Potassium, Visit 4 | t-test, 2 sided | 0.4030 | Other | t-test for mean difference between groups |
| Choride, Screening time point | t-test, 2 sided | 0.9834 | Other | t-test for mean difference between groups |
| Chloride, Visit 4 | t-test, 2 sided | 0.4929 | Other | t-test for mean difference between groups |
| Bicarbonate/CO2 | t-test, 2 sided | 0.1600 | Other | t-test for mean difference between groups |
| Bicarbonate/CO2 at Visit 4 | t-test, 2 sided | 0.6567 | Other | t-test for mean difference between groups |
| Total Bilirubin (mg/dl), 14 days |
|
|
| 0.0777 |
| Other |
t-test for mean difference between groups |
| AST (units/L), 14 days |
|
|
| ALT (units/L), Screening |
|
|
| ALT (units/L), 14 days |
|
|
| 0.8764 |
| Other |
t-test for mean difference between groups |
| ALT, Screening time point | t-test, 2 sided | 0.4853 | Other | t-test for mean difference between groups |
| ALT, Visit 4 | t-test, 2 sided | 0.5853 | Other | t-test for mean difference between groups |
| Alkaline Phosphatase (IU/L), 14 days |
|
|
| t-test, 2 sided |
| 0.4587 |
| Other |
t-test for mean difference between groups |
| Total Protein (g/dl), 14 days |
|
|
| Hemoglobin (g/dl), Screening |
|
|
| Hemoglobin (g/dl), 14 days |
|
|
| Albumin (g/dl), Screening |
|
|
| Albumin (g/dl), 14 days |
|
|
| 0.1957 |
| Other |
t-test for mean difference between groups |
| Hemoglobin, Screening time point | t-test, 2 sided | 0.5938 | Other | t-test for mean difference between groups |
| Hemoglobin, Visit 4 | t-test, 2 sided | 0.7620 | Other | t-test for mean difference between groups |
| Albumin, Screening time point | t-test, 2 sided | 0.7982 | Other | t-test for mean difference between groups |
| Albumin, Visit 4 | t-test, 2 sided | 0.5798 | Other | t-test for mean difference between groups |
| White blood cell count (K/μL), 14 days |
|
|
| Red blood cell count (K/μL), Screening |
|
|
| Red blood cell count (K/μL), 14 days |
|
|
| Platelet count (ct K/ul), Screening |
|
|
| Platelet count (ct K/uL), 14 days |
|
|
| 0.3442 |
| Other |
t-test for mean difference between groups |
| RBC, Screening time point | t-test, 2 sided | 0.4424 | Other | t-test for mean difference between groups |
| RBC, Visit 4 | t-test, 2 sided | 0.4339 | Other | t-test for mean difference between groups |
| Platelet count, Screening time point | t-test, 2 sided | 0.6296 | Other | t-test for mean difference between groups |
| Platelet count, Visit 4 | t-test, 2 sided | 0.9303 | Other | t-test for mean difference between groups |
| Neutrophils (% white blood cells counted), 14 days |
|
|
| Lymphocytes (% white blood cells counted), Screening |
|
|
| Lymphocytes (% white blood cell counted), 14 days |
|
|
| Monocytes (% white blood cells counted), Screening |
|
|
| Monocytes (% white blood cells counted), 14 days |
|
|
| Eosinophils (% white blood cells counted), Screening |
|
|
| Eosinophils (% white blood cells counted), 14 days |
|
|
| Basophils (% white blood cells counted), Screening |
|
|
| Basophils (%) white blood cells counted, 14 days |
|
|
| 0.8892 |
| Other |
t-test for mean difference between groups |
| Lymphocytes, Screening time point | t-test, 2 sided | 0.3021 | Other | t-test for mean difference between groups |
| Lymphocytes, Visit 4 | t-test, 2 sided | 0.6988 | Other | t-test for mean difference between groups |
| Monocytes, Screening time point | t-test, 2 sided | 0.3715 | Other | t-test for mean difference between groups |
| Monocytes, Visit 4 | t-test, 2 sided | 0.6909 | Other | t-test for mean difference between groups |
| Eosinophils, Screening time point | t-test, 2 sided | 0.7857 | Other | t-test for mean difference between groups |
| Eosinophils, Visit 4 | t-test, 2 sided | 0.3409 | Other | t-test for mean difference between groups |
| Basophils, Screening time point | t-test, 2 sided | 0.9142 | Other | t-test for mean difference between groups |
| Basophils, Visit 4 | t-test, 2 sided | 0.6748 | Other | t-test for mean difference between groups |
| 0.6700 |
| Other |
t-test for mean difference between groups |
| Glucose (mg/dl), 14 days |
|
|
| 0.3704 |
| Other |
t-test for mean difference between groups |
| Urea Nitrogen (mg/dl), 14 days |
|
|
| Creatinine (mg/dl), Screening |
|
|
| Creatiniine (mg/dl), 14 days |
|
|
| Serum Uric Acid (mg/dl), Screening |
|
|
| Serum Uric Acid (mg/dl), 14 days |
|
|
| 0.2904 |
| Other |
t-test for mean difference between groups |
| Creatinine, Screening time point | t-test, 2 sided | 0.6700 | Other | t-test for mean difference between groups |
| Creatinine, Visit 4 | t-test, 2 sided | 0.8793 | Other | t-test for mean difference between groups |
| Serum uric acid, Screening time point | t-test, 2 sided | 0.1719 | Other | t-test for mean difference between groups |
| Serum uric acid, Visit 4 | t-test, 2 sided | 0.0913 | Other | t-test for mean difference between groups |
| C-reactive protein (mg/dl), 14 days |
|
|
| 0.2881 |
| Other |
t-test for mean difference between groups |
| Hematocrit (% packed red blood cell volume), 14 days |
|
|
| 0.9415 |
| Other |
t-test for mean difference between groups |
| PAA, Day 1 Hr 4 - Day 1 Baseline |
|
| PAA, Day 4 Hr 4 - Day 1 Baseline |
|
PBA, Day 1 Baseline to Day 4 Hour 2 |
| Mixed Models Analysis |
| <0.0001 |
| Mean Difference (Net) |
| 43.7 |
| Standard Error of the Mean |
| 9.8 |
| 2-Sided |
| 95 |
| 24.2 |
| 63.2 |
Day 1 BL to Day 4 Hour 2; all placebo data were below detectable limits, so comparison not made |
| Other |
| PAA, Day 1 BL to Day 1 Hour 4 | Mixed Models Analysis | <0.0001 | Mean Difference (Net) | 26.1 | Standard Error of the Mean | 4.3 | 2-Sided | 95 | 17.5 | 34.7 | Mean change, BL to Day 1 Hour 2; placebo not analyzed as all values were below detectable limits. | Other | Mean change from baseline to Day 1 Hour 4 |
| PAA, Change from Day 1 BL to Day 4 Hour 4 | Mixed Models Analysis | <0.0001 | Mean Difference (Net) | 57.6 | Standard Error of the Mean | 10.3 | 2-Sided | 95 | 37.2 | 78.1 | Mean change for Drug group reported; placebo data were all below detectable limits. | Other | Mean change, Day 1 BL to Day 4 Hour 4 |